Epidemiological data, statistics on perpetrators of violent crimes and of victims of violence under the influence of drug as well as neurobiological evidence link social stress and drug use. The proposed research aims to characterize the common behavioral and neural features of individuals who experience salient types of social stress and who self-administer psychomotor stimulants and opioids in a compulsive-like manner, and to define the neural circuits for these apparently opposing activities. Ostensibly aversive events such as social defeat stress and euphorogenic effects such as those produced by cocaine or opioids share physiological and corticolimbic circuits. First, experiments are designed to identify the critical behavioral and mesocorticolimbic features of brief episodes of social defeat stress, chronic subordination stress, and impulsive aggressive behavior as potential determinants for the transition to compulsive-like intravenous self-administration of cocaine, d-amphetamine or morphine. We aim to characterize the transition from regulated to dysregulated drug taking by studying the long (>24 h) drug binge as a model. Secondly, the neurobiological mechanisms for the behavioral sensitization that results from repeated episodes of social defeat stress will be characterized with a focus on glutamatergic, GABAergic and serotonergic modulation of mesocorticolimbic dopaminergic pathway. In vivo microdialysis measurements aim to reveal the emerging neural sensitization in the microcircuit consisting of amgydaloid and cortical structures modulating the VTA DA system. Thirdly, neuropharmacological experiments are designed to examine the role of NMDA and AMPA glutamatergic receptos, GABAA receptors, and subtypes of the 5-HT receptor families in modulating activity in the mesocorticolimbic DA pathway for their relevance in sensitization to social stress and in the transition to intense dysregulated cocaine and morphine self-administration in stress-sensitized animals. It is anticipated that the sensitizing effects of social stress experiences can be reversed or protected against by targeting the modulatory influences on the VTA system. Reversal of cross-sensitization from stress may be a means by which to prevent the transition to out-of-control compulsive-like drug taking.